US4994382A - Process for production of pyrrolo-quinoline quinone - Google Patents

Process for production of pyrrolo-quinoline quinone Download PDF

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US4994382A
US4994382A US07/357,668 US35766889A US4994382A US 4994382 A US4994382 A US 4994382A US 35766889 A US35766889 A US 35766889A US 4994382 A US4994382 A US 4994382A
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pyrrolo
quinoline quinone
pqq
medium
cultured
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US07/357,668
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Minoru Ameyama
Osao Adachi
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Ube Corp
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Ube Industries Ltd
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
    • C12P17/182—Heterocyclic compounds containing nitrogen atoms as the only ring heteroatoms in the condensed system
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/822—Microorganisms using bacteria or actinomycetales
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/822—Microorganisms using bacteria or actinomycetales
    • Y10S435/874—Pseudomonas

Definitions

  • the present invention relates to a process for the microbial production of pyrrolo-quinoline quinone (hereinafter referred to as PQQ).
  • PQQ has the following formula: ##STR1## and can be reversibly reduced to a reduced type PQQ (PQQH 2 ) having the following formula: ##STR2##
  • PQQ has an ability to convert apo-type quinoenzymes to the holo-type thereof.
  • PQQ acts as a coenzyme for methanol dehydrogenase in methanol-utilizing bacteria, alcohol dehydrogenase, aldehyde dehydrogenase, glycerol dehydrogenase, glucose dehydrogenase, or the like in acetic acid bacteria.
  • PQQ is also physiologically important as a coenzyme for copper containing amine oxidase of animal, plant or microbial origin, amine dehydrogenase or choline dehydrogenase, or other various kinds of oxidoreductases which are inhibited by carbonyl reagents.
  • PQQ may be a very important substance having vitamin actions because it acts as a coenzyme for important enzymes as described above, taking as an analogy the fact that coenzymes for other oxidoreductases and transferases, such as thiamine pyrrophosphate, nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate, pyridoxal phosphate, flavin adenine dinucleotide, and flavin mononucleotide have to be taken in as vitamin, such as vitamin B 1 , nicotinic acid, vitamin B 6 , and vitamin B 2 , respectively.
  • PQQ is useful for pharmaceutical purposes.
  • the present invention provides a new process for the production of PQQ comprising, culturing a bacterium belonging to the genus Paracoccus, Protaminobacter or Pseudomonas and capable of producing pyrrolo-quinoline quinone in a culture medium to produce the pyrrolo-quinoline quinone in the cultured broth, and recovering the pyrrolo-quinoline quinone from the cultured broth.
  • a process for the production of PQQ comprising culturing the above-mentioned bacterium in a culture medium, to form cultured cells, separating the cells from the cultured broth, resuspending the separated cells in a reaction medium containing precursors of the pyrrolo-quinoline quinone, incubating the reaction medium to produce the pyrrolo-quinoline quinone, and recovering the pyrrolo-quinoline quinone from the reaction medium.
  • FIG. 1 is a calibration chart showing the relationship between an amount of PQQ and a difference of absorption per minute at 600 nm as measured by using a membrane of 0.16 mg as protein ( ⁇ OD600/min./0.16 mg).
  • FIG. 2 is a graph showing a profile of the culturing of Paracoccus denitrificans in Example 1.
  • bacteria are typically used in the present invention:
  • the above-mentioned bacteria (1) and (2) have been deposited at the Institute for Fermentation, Osaka (IFO) in Japan, and can be freely supplied to the public.
  • the bacteria (3) to (7) were isolated by the present invention, and deposited at the Fermentation Research Institute (FRI) in Japan, on April 27, 1984.
  • the bacterium(7) was transferred to the international deposition under the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure on Apr. 25, 1985, and given the number FERM BP-775.
  • microorganisms (1) are gram negative rod, (2) are motile, (3) have catalase, oxidase and urease activities, (4) do not form indole, (5) utilize methanol and ethanol, (6) have an optimum pH of 6.8 to 7.3, and (7) have an optimum temperature of 30° C.
  • these microorganisms are identified as methanolutilizable Pseudomonas bacteria. These bacteria are different from Pseudomonas already described, and therefore, are new strains.
  • one of the above-mentioned bacteria capable of producing PQQ is cultured in a culture medium.
  • the culture medium is preferably a liquid medium, and contains a carbon source and nitrogen source.
  • the carbon source is, for example, methanol, methylamine, or other substrates from which C 1 -compound can be generated biologically.
  • the medium preferably contains methanol as the carbon source at a concentration of 0.1 to 5.0%, preferably 0.5 to 3.0% by weight. All of the methanol may be added to the medium before the start of culturing, or it may be added step by step or continuously during culturing.
  • the nitrogen source includes organic nitrogen sources such as amino acids, nucleic acids, protein hydrolyzates, yeast extract, corn steep liquor, and inorganic nitrogen sources such as ammonium salts, ammonia water, gaseous ammonia, and nitrates.
  • organic nitrogen sources such as amino acids, nucleic acids, protein hydrolyzates, yeast extract, corn steep liquor
  • inorganic nitrogen sources such as ammonium salts, ammonia water, gaseous ammonia, and nitrates.
  • the above-mentioned nitrogen sources may be used alone or in combination.
  • the concentration of nitrogen source varies according to the kind of nitrogen source used, and is preferably within 0.05% to 0.5% by weight.
  • the culturing is preferably carried out under the aerobic condition which is accomplished by aeration and agitation of the medium in a fermentor, or by shaking a culture flask containing the medium.
  • the temperature for culturing is generally 0° C. to 40° C., preferably 20° C. to 35° C.
  • the pH of the medium is generally 2 to 9, preferably 5.5 to 8.0.
  • the culturing time is generally 20 to 150 hours, preferably 50 to 100 hours. In the present embodiment, PQQ is accumulated in the cultured broth.
  • one of the above-mentioned bacteria is cultured in a culture medium, and the cultured cells are separated from the cultured broth. The separated cells are then resuspended in a reaction medium in which PQQ is accumulated.
  • the culture medium is preferably the same as the culture medium described in the first embodiment.
  • the pH and temperature for culturing in the second embodiment are preferably the same as those used in the first embodiment.
  • the culturing time is preferably 5 to 20 hours.
  • the reaction medium contains precursors of PQQ, which comprise at least one carbon source, for example, alcohols such as methanol or ethanol, or sugars such as mannitol, fructose or glucose, and at least one amino acid such as glutamic acid, aspartic acid, alanine, ornithine, tyrosine, and 3,4-dihydroxyphenylalanine (DOPA).
  • the concentration of the carbon source is preferably 0.5 to 3.0% by weight, and the concentration of the amino acid is preferably 0.05 to 0.5% by weight.
  • the reaction medium can contain a buffer, such as a phosphate buffer, to maintain the pH within the preferable range.
  • the pH and temperature for the reaction are preferably the same as those used for the culturing.
  • the reaction is carried out under the aerobic condition which is accomplished by aeration and agitation of the reaction medium in a reaction vessel, or by shaking a reaction flask containing the reaction medium.
  • PQQ accumulated in the cultured broth in the first embodiment or in the reaction medium in the second embodiment is recovered by conventional processes such as ion exchange chromatography, gel filtration, solvent extraction, affinity chromatography, or a combination thereof.
  • the assaying of PQQ for coenzyme activity and the assay of a concentration of PQQ produced in the cultured broth or reaction medium are carried out according to the following method.
  • the method is carried out using an apoenzyme of quinoenzyme, which may be prepared from a mutant of Pseudomonas aeruginosa which lacks D-glucose dehydrogenase activity (see FEBS Letters, Vol. 130, 179-183, 1981).
  • the mutant cannot produce PQQ, but will produce and accumulate apoenzyme of D-glucose dehydrogenase to a normal level in the cell membrane.
  • a calibration chart showing a relationship of a concentration of PQQ and the enzyme activity expressed is prepared within a range wherein the strength of the enzyme activity is proportional to the concentration of the PQQ, using standard chemically synthesized PQQ.
  • An example of the calibration chart is shown in FIG. 1.
  • the amount of PQQ in a sample is determined by comparing the strength of the enzyme activity measured for the sample with the calibration chart.
  • the amount of PQQ may be also determined in the same manner as described above using an apoenzyme of any other quinoenzyme.
  • the amount of PQQ can be determined by a high performance liquid chromatography.
  • FIG. 2 represents a profile of the culturing, wherein an amount of PQQ accumulated in the medium reaches to the maximum point during the period from the late logarithmic phase to the early stationary phase.
  • the ordinate axis represents the change of absorption per minute, which represents a glucose dehydrogenase activity, in turn, represents an amount of PQQ in the medium.
  • a sample of the medium was obtained at any predetermined time, and centrifuged to obtain a supernatant.
  • the supernatant (0.1 ml) was added to 33 micro grams of a cell membrane fraction containing apo-D-glucose dehydrogenase to obtain 0.11 ml of a mixture, and the mixture was incubated at 30° C. for 30 minutes to allow the conversion of the apo-D-glucose dehydrogegase to the holoenzyme.
  • the growth of the microorganism was monitored by absorbance at 600 nm of the cultured medium.
  • the combined fraction containing PQQ was subjected to liquid chromatographic analysis under the following condition.
  • the result of the analysis showed be the same retention time (13 minutes) for the fraction obtained as above, and for the chemically synthesized PQQ.
  • Example 1 was repeated using the microorganisms set forth in Table 3, and PQQ accumulated in the cultured medium in the amount set forth in the same Table.
  • Example 2 30 l of a medium having the same composition as described in Example 1 was incorporated in a 50 l fermentor, and the medium was inoculated with an inoculam containing cells of Pseudomonas Nl-1 (FERM P-7596), aerated at 30 l/min., and agitated at 500 rpm. A concentration of methanol in the medium was maintained at 1% by adding methanol during the culturing. The culturing was continued for 50 hours. The concentration of PQQ reached 30 ⁇ g/ml.
  • Example 1 was repeated except that the concentration of methanol was varied as described in Table 4. PQQ was produced in the concentration set forth in the same Table.

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  • Organic Chemistry (AREA)
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  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Genetics & Genomics (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Enzymes And Modification Thereof (AREA)
US07/357,668 1984-05-29 1989-05-26 Process for production of pyrrolo-quinoline quinone Expired - Fee Related US4994382A (en)

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JP59-107406 1984-05-29
JP59107406A JPS60251895A (ja) 1984-05-29 1984-05-29 ピロロキノリンキノンの製造方法

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5346819A (en) * 1992-02-24 1994-09-13 Toyo Boseki Kabushiki Kaisha Glycerol dehydrogenase, process for its production and its use
US5429940A (en) * 1989-11-13 1995-07-04 Mitsubishi Gas Chemical Company Process for producing oxazopyrroloquinolines, novel oxazopyrroloquinolines, and use of oxazopyrroloquinolines
US5484708A (en) * 1993-04-08 1996-01-16 Boehringer Mannheim Gmbh Method for the colorimetric determination of an analyte with a PQQ-dependent dehydrogenase
US6200773B1 (en) * 1998-09-28 2001-03-13 Lifescan, Inc. Diagnostics based on tetrazolium compounds
US6316231B1 (en) 1998-09-11 2001-11-13 Archer-Daniels-Midland Company Bacterial strains for the production of 2-keto-L-gulonic acid
US20020006665A1 (en) * 2000-04-05 2002-01-17 D'elia John Ketogulonigenium endogenous plasmids
US20020039761A1 (en) * 2000-04-05 2002-04-04 John D' Elia Ketogulonigenium shuttle vectors
US6541239B1 (en) 1996-10-24 2003-04-01 Archer-Daniels-Midland Company Bacterial strains and use thereof in fermentation processes for 2-keto-L-gulonic acid production
US20040053352A1 (en) * 1998-09-28 2004-03-18 Tianmei Ouyang Diagnostics based on tetrazolium compounds
US20040119037A1 (en) * 2002-07-16 2004-06-24 Mentzer Mark A. Electro-optic fluid quantity measurement system
US20060094099A1 (en) * 2004-10-28 2006-05-04 Zhixin Shao Inactivated enzyme variants and associated process and reagent system
US8362436B1 (en) 2006-03-14 2013-01-29 Advanced Precision Inc. Electro-optic fluid quantity measurement system
KR20160068313A (ko) 2014-12-05 2016-06-15 주식회사 성운바이오 신규한 하이포마이크로비움속 미생물 및 이를 이용한 피로로퀴놀린 퀴논의 제조방법
CN110698472A (zh) * 2019-09-11 2020-01-17 北大方正集团有限公司 一种吡咯喹啉醌的纯化方法
KR102120670B1 (ko) 2019-01-03 2020-06-10 주식회사 누베파마 돌연변이 균주를 이용한 항산화 물질 생산 방법
CN112194658A (zh) * 2020-10-23 2021-01-08 内蒙古拜克生物有限公司 一种吡咯喹啉醌的分离纯化方法
CN113981021A (zh) * 2021-05-21 2022-01-28 江苏一鸣生物科技有限公司 一种通过嗜氨副球菌发酵合成pqq的方法

Families Citing this family (5)

* Cited by examiner, † Cited by third party
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US5344768A (en) * 1985-04-24 1994-09-06 Mitsubishi Gas Chemical Co., Inc. Process for the preparation of pyrrolo-quinoline quinone
EP0206471B1 (en) * 1985-04-24 1992-10-14 Mitsubishi Gas Chemical Company, Inc. Process for preparation of pyrrolo-quinoline quinone
JPS61247397A (ja) * 1985-04-24 1986-11-04 Mitsubishi Gas Chem Co Inc ピロロキノリンキノンの製造方法
CN105294687B (zh) * 2015-12-02 2016-11-16 郑州轻工业学院 离子对双水相萃取分离吡咯喹啉醌的方法
CN105624084B (zh) * 2016-01-28 2019-04-16 福建师范大学 定向驯化选育高产吡咯喹啉醌的甲基营养菌

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Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5429940A (en) * 1989-11-13 1995-07-04 Mitsubishi Gas Chemical Company Process for producing oxazopyrroloquinolines, novel oxazopyrroloquinolines, and use of oxazopyrroloquinolines
US5346819A (en) * 1992-02-24 1994-09-13 Toyo Boseki Kabushiki Kaisha Glycerol dehydrogenase, process for its production and its use
US5614374A (en) * 1992-02-24 1997-03-25 Toyo Boseki Kabushiki Kaisha Glycerol dehydrogenase, process for its production and its use
US5484708A (en) * 1993-04-08 1996-01-16 Boehringer Mannheim Gmbh Method for the colorimetric determination of an analyte with a PQQ-dependent dehydrogenase
US6541239B1 (en) 1996-10-24 2003-04-01 Archer-Daniels-Midland Company Bacterial strains and use thereof in fermentation processes for 2-keto-L-gulonic acid production
US6511820B1 (en) 1998-09-11 2003-01-28 Archer-Daniels-Midland Company Bacterial strains for the production of Pyrroloquinoline Quinone
US6316231B1 (en) 1998-09-11 2001-11-13 Archer-Daniels-Midland Company Bacterial strains for the production of 2-keto-L-gulonic acid
US6506583B1 (en) 1998-09-11 2003-01-14 Archer-Daniels-Midland Company Bacterial strains for the production of 2-keto-L-gulonic acid
US6562584B1 (en) 1998-09-11 2003-05-13 Archer-Daniels-Midland Company Bacterial strains for the production of 2-keto-L-gulonic acid
US7144709B2 (en) 1998-09-28 2006-12-05 Lifescan, Inc. Diagnostics based on tetrazolium compounds
US6200773B1 (en) * 1998-09-28 2001-03-13 Lifescan, Inc. Diagnostics based on tetrazolium compounds
US7011954B2 (en) 1998-09-28 2006-03-14 Lifescan, Inc. Diagnostics based on tetrazolium compounds
US20050112712A1 (en) * 1998-09-28 2005-05-26 Lifescan, Inc. Diagnostics based on tetrazolium compounds
US20040053352A1 (en) * 1998-09-28 2004-03-18 Tianmei Ouyang Diagnostics based on tetrazolium compounds
US7053196B2 (en) 2000-04-05 2006-05-30 Archer-Daniels-Midland Company Ketogulonigenium endogenous plasmids
US7053197B2 (en) 2000-04-05 2006-05-30 Archer-Daniels-Midland Company Ketogulonigenium endogenous plasmids
US20020006665A1 (en) * 2000-04-05 2002-01-17 D'elia John Ketogulonigenium endogenous plasmids
US20020039761A1 (en) * 2000-04-05 2002-04-04 John D' Elia Ketogulonigenium shuttle vectors
US20030077830A1 (en) * 2000-04-05 2003-04-24 Archer-Daniels-Midland Company Ketogulonigenium endogenous plasmids
US20030073224A1 (en) * 2000-04-05 2003-04-17 Archer-Daniels-Midland Company Ketogulonigenium endogenous plasmids
US7030233B2 (en) 2000-04-05 2006-04-18 Archer-Daniels-Midland Company Ketogulonigenium endogeneous plasmids
US7033824B2 (en) 2000-04-05 2006-04-25 Archer-Daniels-Midland Company Ketogulonigenium shuttle vectors
US20030087440A1 (en) * 2000-04-05 2003-05-08 Archer-Daniels-Midland Company Ketogulonigenium endogenous plasmids
US6831290B2 (en) 2002-07-16 2004-12-14 Strube, Inc. Electro-optic fluid quantity measurement system
US20040119037A1 (en) * 2002-07-16 2004-06-24 Mentzer Mark A. Electro-optic fluid quantity measurement system
US20060094099A1 (en) * 2004-10-28 2006-05-04 Zhixin Shao Inactivated enzyme variants and associated process and reagent system
US7172890B2 (en) * 2004-10-28 2007-02-06 Roche Diagnostics Gmbh Inactivated enzyme variants and associated process and reagent system
US8362436B1 (en) 2006-03-14 2013-01-29 Advanced Precision Inc. Electro-optic fluid quantity measurement system
KR20160068313A (ko) 2014-12-05 2016-06-15 주식회사 성운바이오 신규한 하이포마이크로비움속 미생물 및 이를 이용한 피로로퀴놀린 퀴논의 제조방법
KR102120670B1 (ko) 2019-01-03 2020-06-10 주식회사 누베파마 돌연변이 균주를 이용한 항산화 물질 생산 방법
CN110698472A (zh) * 2019-09-11 2020-01-17 北大方正集团有限公司 一种吡咯喹啉醌的纯化方法
CN112194658A (zh) * 2020-10-23 2021-01-08 内蒙古拜克生物有限公司 一种吡咯喹啉醌的分离纯化方法
CN113981021A (zh) * 2021-05-21 2022-01-28 江苏一鸣生物科技有限公司 一种通过嗜氨副球菌发酵合成pqq的方法
CN113981021B (zh) * 2021-05-21 2023-09-26 江苏一鸣生物科技有限公司 一种通过嗜氨副球菌发酵合成pqq的方法

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DE3582902D1 (de) 1991-06-27
JPS60251895A (ja) 1985-12-12
EP0164943A2 (en) 1985-12-18
EP0164943A3 (en) 1987-12-09
EP0164943B1 (en) 1991-05-22
JPH0516833B2 (enrdf_load_stackoverflow) 1993-03-05

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